Tubulointerstitial injury accompanies most forms of glomerular disease and hypertensive renal disease, and is also a major complication of cyclosporine therapy. Understanding the pathogenesis of the tubulointerstitial injury is critical given that it is the degree of tubulointerstitial injury that best correlates with the renal function and the risk for progression. The central hypothesis of this proposal is that osteopontin is a monocyte chemotactic/adhesive protein that is expressed by tubules in a variety of renal diseases and mediates the local macrophage infiltration and tubular injury. In preliminary data we have shown that osteopontin MRNA and protein are expressed by distal tubules in angiotensin II-mediated hypertensive injury, two models of glomerulonephritis, and cyclosporine nephropathy in rats. In the AII- mediated model the osteopontin expression was shown to correlate with sites of macrophage accumulation and tubular injury. We now propose to 10 perform sequential histologic studies in the glomerulonephritis models and cyclosporine nephropathy to determine when osteopontin is expressed and to correlate this with infiltrating leukocyte populations and tubulointerstitial injury; 2) to determine if the osteopontin expression in this model, and in ALL-mediated hypertension, is mediated by angiotensin type I or II receptors, and 3) to determine the effect in these models of blocking osteopontin action by infusing either synthetic osteopontin peptides or specific blocking antibodies. We believe that determining the role of osteopontin in these models may provide insight into the mechanisms mediating tubulointerstitial injury in renal disease and may provide a rationale for future therapies for progressive renal disease.